1. Field of the Invention
The present invention relates generally to the fields of cellular biology and oncology. More particularly, it concerns AGR2 and C4.4A-binding antibodies and methods of their use in anti-cancer therapies.
2. Description of Related Art
Anterior Gradient 2 (AGR2 [also called hAG-2 (Thompson and Weigel, 1998) or Gob-4 (Komiya et al., 1999)]) is the human orthologue of the Xenopus laevis, XAG-2. XAG-2 is secreted and takes part in ectodermal patterning of the frog embryo and in amphibian limb regeneration by interacting with the receptor Prod-1 of the Ly6 superfamily (Aberger et al., 1998; Kumar et al., 2007; da Silva et al., 2002). However, there is no human homologue of Prod-1. It is unknown whether AGR2 functions through a receptor on the cell surface or functions within cells in humans. The tissue distribution of AGR2 in healthy adult humans indicates that it is restricted to organs possessing mucin producing cells. A mouse genetic deletion model of AGR2 showed alterations in mucin synthesis (Park et al., 2009). Other studies have supported the concept that AGR2 possesses sequence similarity to the protein disulfide isomerase (PDI) family (Zhao et al., 2010; Altschul et al., 1997; Persson et al., 2005; Gupta et al., 2012). A member of the PDI protein family may catalyze formation, reduction and isomerization of disulfide bonds, thereby stabilizing intermediate conformations during protein maturation in the ER (Persson et al., 2005). However, a role of AGR2 in protein synthesis in normal cells does not resemble its actions in amphibians and also does not explain its observed roles in cancer.
AGR2 has been reported to bind to dystroglycan-1 (DAG-1) and C4.4A based on yeast two-hybrid results (Fletcher et al., 2003). However, no evidence was provided to support the interactions of these molecules in mammalian cells or to demonstrate the biological function of these interactions. AGR2 is expressed in a wide variety of tumors formed in different tissues with diverse patterns of genetic alterations including pancreatic ductal adenocarcinoma (PDAC) (Ramachandran et al., 2008) and cancers of the breast (Thompson and Weigel, 1998; Fletcher et al., 2003), prostate (Zhang et al., 2005), lung (Zhu et al., 2007), and colorectum (Smirnov et al., 2005). AGR2 supports aggressive growth and metastasis of a variety of cancer cells (Liu et al., 2005; Innes et al., 2006; Barraclough et al., 2009). Hence, AGR2 and its receptor may serve as useful therapeutic targets.